Polycystic kidney disease: The complexity of planar cell polarity and signaling during tissue regeneration and cyst formation

AbstractAutosomal Dominant Polycystic Kidney Disease (ADPKD) is an inherited systemic disease with intrarenal cystogenesis as its primary characteristic. A variety of mouse models provided information on the requirement of loss of balanced polycystin levels for initiation of cyst formation, the role of proliferation in cystogenesis and the signaling pathways involved in cyst growth and expansion. Here we will review the involvement of different signaling pathways during renal development, renal epithelial regeneration and cyst formation in ADPKD, focusing on planar cell polarity (PCP) and oriented cell division (OCD). This will be discussed in context of the hypothesis that aberrant PCP signaling causes cyst formation. In addition, the role of the Hippo pathway, which was recently found to be involved in cyst growth and tissue regeneration, and well-known for regulating organ size control, will be reviewed. The fact that Hippo signaling is linked to PCP signaling makes the Hippo pathway a novel cascade in cystogenesis. The newly gained understanding of the complex signaling network involved in cystogenesis and disease progression, not only necessitates refining of the current hypothesis regarding initiation of cystogenesis, but also has implications for therapeutic intervention strategies. This article is part of a Special Issue entitled: Polycystic Kidney Disease

Hepatic Cyst Infection During Use of the Somatostatin Analog Lanreotide in Autosomal Dominant Polycystic Kidney Disease: An Interim Analysis of the Randomized Open-Label Multicenter DIPAK-1 Study

Introduction and Aims: The DIPAK-1 Study investigates the reno- and hepatoprotective efficacy of the somatostatin analog lanreotide compared with standard care in patients with later stage autosomal dominant polycystic kidney disease (ADPKD). During this trial, we witnessed several episodes of hepatic cyst infection, all during lanreotide treatment. We describe these events and provide a review of the literature. Methods: The DIPAK-1 Study is an ongoing investigator-driven, randomized, controlled, open-label multicenter trial. Patients (ADPKD, ages 18–60 years, estimated glomerular filtration rate 30–60 mL/min/1.73 m2) were randomized 1:1 to receive lanreotide 120 mg subcutaneously every 28 days or standard care during 120 weeks. Hepatic cyst infection was diagnosed by local physicians. Results: We included 309 ADPKD patients of which seven (median age 53 years [interquartile range: 48–55], 71% female, median estimated glomerular filtration rate 42 mL/min/1.73 m2 [interquartile range: 41–58]) developed eight episodes of hepatic cyst infection during 342 patient-years of lanreotide use (0.23 cases per 10 patient-years). These events were limited to patients receiving lanreotide (p < 0.001 vs. standard care). Baseline characteristics were similar between subjects who did or did not develop a hepatic cyst infection during lanreotide use, except for a history of hepatic cyst infection (29 vs. 0.7%, p < 0.001). Previous studies with somatostatin analogs reported cyst infections, but did not identify a causal relationship. Conclusions: These data suggest an increased risk for hepatic cyst infection during use of somatostatin analogs, especially in ADPKD patients with a history of hepatic cyst infection. The main results are still awaited to fully appreciate the risk–benefit ratio. ClinicalTrials.gov identifier: NCT 01616927

STAT5 drives abnormal proliferation in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) leads to renal failure. The hallmark of ADPKD is increased epithelial proliferation, which has been proposed to be due to atypical signaling including abnormal JAK-STAT activity. However, the relative contribution of JAK-STAT family members in promoting proliferation in ADPKD is unknown. Here, we present siRNA JAK-STAT-focused screens discovering a previously unknown proliferative role for multiple JAK-STAT components (including STAT1, STAT2, STAT4, STAT5a, and STAT5b). Amongst these, we selected to study the growth hormone/growth hormone receptor/STAT5-axis because of its known role as a regulator of growth in nonrenal tissues. Loss of STAT5 function, facilitated by pharmacological inhibition or siRNAs, significantly reduced proliferation with an associated reduction in cyst growth in vitro. To study whether STAT5 is abnormally activated in vivo, we analyzed its expression using two independent mouse models of ADPKD. STAT5 was nuclear, thus activated, in renal epithelial cyst lining cells in both models. To test whether forced activation of STAT5 can modulate proliferation of renal cells in vivo, irrespective of the Pkd1 status, we overexpressed growth hormone. These mice showed increased STAT5 activity in renal epithelial cells, which correlated with de novo expression of cyclin D1, a STAT5 target gene. Chromatin immunoprecipitation experiments revealed that STAT5 transcriptionally activated cyclin D1 in a growth hormone-dependent fashion, thus providing a mechanism into how STAT5 enhances proliferation. Finally, we provide evidence of elevated serum growth hormone in Pkd1 mutant mice. Thus, the growth hormone/STAT5 signaling axis is a novel therapeutic target in ADPKD

A comprehensive mouse kidney atlas enables rare cell population characterization and robust marker discovery

The kidney's cellular diversity is on par with its physiological intricacy; yet identifying cell populations and their markers remains challenging. Here, we created a comprehensive atlas of the healthy adult mouse kidney (MKA: Mouse Kidney Atlas) by integrating 140.000 cells and nuclei from 59 publicly available single-cell and single-nuclei RNA-sequencing datasets from eight independent studies. To harmonize annotations across datasets, we built a hierarchical model of the cell populations. Our model allows the incorporation of novel cell populations and the refinement of known profiles as more datasets become available. Using MKA and the learned model of cellular hierarchies, we predicted previously missing cell annotations from several studies. The MKA allowed us to identify reproducible markers across studies for poorly understood cell types and transitional states, which we verified using existing data from micro-dissected samples and spatial transcriptomics.</p

Lithium, an inhibitor of cAMP-induced inositol 1,4,5-trisphosphate accumulation in Dictyostelium discoideum, inhibits activation of guanine-nucleotide-binding regulatory proteins, reduces activation of adenylylcyclase, but potentiates activation of guanyl

Li+ drastically alters pattern formation in Dictyostelium by inhibiting cAMP-induced prespore-gene expression and promoting cAMP-induced prestalk-gene expression. We reported previously that Li+ inhibits inositol monophosphatases in this organism and strongly reduces basal and cAMP-stimulated inositol 1,4,5-trisphosphate levels. We show here that Li+ also reduces cAMP-induced accumulation of cAMP, but promotes cAMP-induced accumulation of cGMP. This effect is not due to inhibition of cGMP hydrolysis or inhibition of adaptation and may therefore reflect stimulation of guanylyl-cyclase activation. Li+ does not affect the binding of cAMP to surface receptors but interferes with the interaction between receptors and guanine-nucleotide-binding regulatory (G) proteins. These effects are complex; in the absence of Mg2+, Li+ increases guanosine 5'-[γ-thio]triphosphate(GTP[S])-binding activity to similar levels as 1 mM Mg2+. However, while Mg2+ potentiates cAMP-induced stimulation of GTP[S]-binding activity, Li+ effectively inhibits stimulation. Li+ also inhibits cAMP-stimulated, but not basal high-affinity GTP-ase activity, indicating an inhibitory effect on cAMP-induced activation of G-proteins. Our data suggest that in addition to inositolphosphate metabolism, the activation of G-proteins may be a second biochemical target for Li+ effects on pattern formation and signal transduction in Dictyostelium.

Tubular flow activates magnesium transport in the distal convoluted tubule

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Lithium ions induce prestalk-associated gene expression and inhibit prespore gene expression in Dictyostelium discoideum

We investigated the effect of Li+ on two types of cyclic AMP-regulated gene expression and on basal and cyclic AMP-stimulated inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) levels. Li+ effectively inhibits cyclic AMP-induced prespore gene expression, half-maximal inhibition occurring at about 2mM-LiCl. In contrast, Li+ (1-3 mM) promotes the cyclic AMP-induced increase of cysteine proteinase-2 mRNA levels, and induces the expression of this prestalk-associated gene in the absence of cyclic AMP stimuli. At concentrations exceeding 4-5 mM, LiCl inhibits cysteine proteinase-2 gene expression. LiCl reduces basal Ins(1,4,5)P3 levels and decreases the cyclic AMP-induced accumulation of Ins(1,4,5)P3; both effects occur half-maximally at 2-3 mM-LiCl. These results indicate that the induction of the cysteine proteinase-2 gene by Li+ is not due to elevated levels of Ins(1,4,5)P3. It is, however, possible that inhibition of prespore gene expression by Li+ is caused by Li+-induced reduction of basal and/or stimulated Ins(1,4,5)P3 levels.